Eighty to ninety percent of colorectal cancers involve aberrant activation of the Wnt/-catenin signaling pathway, which is associated with tumor initiation, proliferation, progression and poor prognosis. Wnt signaling, in particular the nuclear functions of -catenin have also been shown to be important in the maintenance, proliferation and differentiation of both embryonic and adult somatic stem cells. Our pharmacogenomic studies clearly demonstrate that the coactivators CBP and p300 have distinct functions in regulating the expression of Wnt/-catenin regulated genes including survivin, EGFR, VEGF, EphB2, S100A4,CD44, connexin 43 and cyclin D1, which play important roles in initiation, proliferation, angiogenesis, metastasis and drug resistance. We have developed and validated a model that posits that CBP/-catenin-mediated transcription is critical for proliferation without differentiation (e.g. in cancer and stem cells) whereas a switch of coactivator usage to p300/-catenin is the essential first step to initiate differentiation with a more limited proliferative capacity. Our central hypothesis is that increased CBP/-catenin/TCF4 driven transcription at the expense of p300/-catenin/TCF4-mediated transcription is associated with colon cancer development, and is essential for tumor relapse, drug resistance, metastases and poor prognosis in patients with colon cancer. Importantly, we have developed the first specific small molecule antagonists of the CBP/-catenin interaction, ICG-001 and C82/C88 (aka PRI-724), which disrupt a subset of Wnt/-catenin driven transcription. We propose to test our hypothesis both pre-clinically in vitro and in vivo and clinically in a randomized phase II trial in combinatin with FOLFOX/Bevacizumab in patients with newly diagnosed metastatic colorectal cancer.